A retrovirus termed human immunodeficiency virus (HIV), related to members of the lentivirus family is etiologically associated with acquired immunodeficiency syndrome (AIDS). Studies of HIV genome structure has shown extensive heterogeneity among different isolates, and it is likely that biological function correspondingly varies among divergent HIVs. This information and the fact that many individuals infected with HIV have not yet developed AIDS raises the possibility that virulent and relatively nonvirulent strains may exist. In preliminary studies we have isolated a panel of HIVs and demonstrated some to be heterogenous antigenically and in their biological properties (cell tropism, RT thermal stability, toxicity, giant cell formation, replication). We have also examined the effect HIV infection has on cellular membrane-associated biochemical pathways (ion influx, lipid metabolism) in attempts to understand how virulent HIVs injure helper/inducer T-lymphocytes. Increased influx of ions (i.e., Ca++), shutdown of phospholipid metabolism, and enhanced triacylglyceride synthesis were some early events temporally associated with cell injury. Based on these findings, certain membrane-reactive compounds added to HIV-infected cells were found to partially prevent cell injury. The overall goal of the research proposed herein is to understand the biology and biochemistry of cytopathic HIVs. We aim specifically to 1) finish defining the biological properties (cell tropism, virus-cell binding, virus replication, cytotoxicity, cell fusion, viral interference) of diverse isolates of HIV, 2) to determine what biological properties correlate with virulence in vivo and whether virulent and relatively nonvirulent HIV strains do exist (following virus donors for disease progression), 3) to assess what genetic sequences of HIVs determine specific biological properties and virulence (molecularly cloning prototype HIVs and constructing intergenic and deletion mutants), and 4) to continue our studies of the molecular mechanism(s) by which virulent HIVs injure cells and ways to reverse it (studies of lipid metabolism). These goals are extensive and three independent investigators are committed to this project, offering expertise in retroviral (and HIV) biology and biochemistry, molecular biology, and cellular biochemistry.